Rafal Ploski

Juvenile idiopathic arthritis (JIA) is primarily associated with HLA-DR8 but not DQ4 on the DR8-DQ4 haplotype

Background: Juvenile idiopathic arthritis (JIA) is strongly associated with the DR8-DQ4 haplotype. The genes encoding DR8 and DQ4 are in strong linkage disequilibrium (LD) and occur together on the same HLA haplotype in almost all patients and controls. Because of the strong LD it is not clear whether DR8, DQ4, or both, are primarily associated with JIA. Objective: To unveil the primary association of JIA—that is, with DR8 or DQ4. Methods: DRB1, DQA1, and DQB1 alleles of 585 Norwegian and 47 Polish unrelated patients with JIA (categorised as pauciarticular and rheumatoid factor negative polyarticular JIA), and of 3155 Norwegian and 158 Polish unrelated controls, were typed using a polymerase chain reaction or oligonucleotide hybridisation and sequence-specific primers method. Results: Several haplotypes which encoded DR8 (that is, carried DRB1*08) and which did not encode DQ4 (that is, did not carry DQA1*0401) were found. Such haplotypes were found in three Norwegian patients and two controls (p=0.029). In the Polish population such haplotypes were found among four patients with JIA and two controls (p=0.025). No haplotypes which carried DQA1*0401 and DQB1*0402 in the absence of DRB1*08 were found, either among patients with JIA (Polish and Norwegian) or among the controls (Polish). Conclusion: On the DR8-DQ4 haplotype the DRB1*08 allele is primarily associated with JIA.

Lack of association with T-cell receptor TCRBV6S1*2 allele in HLA-DQA1*0101-positive Norwegian juvenile chronic arthritis patients

Juvenile chronic arthritis (JCA) encompasses a group of HLA-associated rheumatic disorders, of probable autoimmune nature with onset in childhood or early adolescence. Most patients belong to the pauciarticular subset. Earlier observations suggested that among panciarticular JCA patients HLA-DQAI*OIO1 was positively associated with progression to polyarticular disease and negatively associated with chronic iridocyclitis (van Kerckhove et al. 1991). In a recent study of Norwegian JCA patients, these results were confirmed, and, furthermore, it was concluded that DRB1 *0101 (or the closely associated DQA1 *0101) may define a separate subset of JCA (Ploski et al. 1993). It was recently reported that the frequency of the T-cell receptor TCRBV6SI*2 allele, one of the two known alleles of the TCRBV6S1 gene, was increased in DQA1 *0101-positive patients with pauciarticular JCA relative to HLA-DQA1 matched healthy controls (Maksymowych et al. 1991, 1992). Further studies by the same group revealed a reduced expression of the TCRBV6S1 *2 allele compared to the TCRBV6S1 1 allele, indicating a functional significance of the TCRBV6S1 polymorphism. It was suggested that the substitution of a conserved cysteine at amino acid position 92 by arginine, found in TCRBV6S1 *2, interfered with the formation of disulfide bonds and thus prevented a correct folding of the protein (Luyrink et al., 1993). The objective of the present study was to investigate a possible TCRBV6S1 *2 role in conferring susceptibility to JCA among DQAl*OlOl-positive patients. A1-

A gene in the telomeric HLA complex distinct from HLA-A is involved in predisposition to juvenile idiopathic arthritis (JIA)

OBJECTIVEnJuvenile idiopathic arthritis (JIA) is associated with particular alleles at 3 different HLA loci: HLA-A, HLA-DR/DQ, and HLA-DP. These associations are independent of each other (i.e., they cannot be explained by the known linkage disequilibrium between alleles at these loci). The purpose of this study was to look for additional JIA susceptibility genes in the HLA complex.nnnMETHODSnOne hundred two Norwegian JIA patients and 270 healthy individuals, all carrying the DQ4;DR8 haplotype, were investigated by scanning approximately 10 megabases of DNA covering the HLA complex with microsatellite polymorphisms. An expectation-maximization algorithm was used to estimate haplotype frequencies, and the distribution of microsatellite alleles on the high-risk DQ4;DR8 haplotype was compared between patients and controls, to exclude effects secondary to linkage disequilibrium with these susceptibility genes.nnnRESULTSnAllele 5 at the microsatellite locus D6S265 (D6S265* 5), 100 kb centromeric of HLA-A, showed a strong positive association with the disease (odds ratio 4.7, corrected P < 10(-6)). Haplotype analysis demonstrated that the D6S265*5 association was not caused by linkage disequilibrium to the gene encoding HLA-A*02, which has previously been reported to be associated with JIA. Instead, our data suggested that a gene in linkage disequilibrium with D6S265*5, but distinct from HLA-A*02, is involved in the predisposition to JIA.nnnCONCLUSIONnWe found that D6S265*5 could be a marker for an additional susceptibility gene in JIA which is distinct from A*02, adding to the risk conferred by DQ4;DR8.